Carvedilol, the first beta blocker labeled in the United States for the treatment of heart failure, has been shown to improve left ventricular ejection fraction and may reduce mortality. Carvedilol is chemically known as 1-(9H-carbazol-4yloxy)-3-[[2-(2-methoxyphenoxy)-ethyl]amino]-propan-2-ol, which has the following structure (I).

Carvedilol is disclosed in U.S. Pat. No. 4,503,067 to Wiedemann et al. Carvedilol is indicated in the management of congestive heart failure (CHF), as an adjunct to conventional treatments (ACE inhibitors and diuretics). Currently, carvedilol is used for treating patients suffering with hypertension, congestive heart failure and angina. The use of carvedilol has been shown to provide additional morbidity and mortality benefits in CHF (Packer et al., 2002).
Carvedilol is synthesized as a racemic mixture of R (+) and S (−) enantiomers for incorporation in medication that is available commercially as a free base. The free base exhibits nonselective beta.-adrenoreceptor blocking activity by virtue of the S (−) enantiomer and also exhibits alpha.-adrenergic blocking activity by virtue of both R (+) and S(−) enantiomers.
Carvedilol contains an α-hydroxyl secondary amine functional group, which has a pKa of 7.8. Carvedilol exhibits predictable solubility behavior in neutral or alkaline media, i.e. above pH of 9.0, the solubility of carvedilol is relatively low (<1 μg/ml). The solubility of carvedilol increases with decreasing pH and reaches a plateau near pH=5, i.e. where saturation solubility is about 23 μg/ml. at pH=7 and about 100 μg/ml at pH=5 at room temperature. At lower pH values (i.e. at a pH of 1 to 4 in various buffer systems), solubility of carvedilol is limited by the solubility of its protonated salts.
The presence of the α-hydroxyl secondary amine group in the carvedilol chemical structure confers a propensity upon the compound to chemically react with excipients normally included in a dosage form to aid manufacture, maintain quality, or enhances dissolution rate. For example, the α-hydroxyl secondary amine group of carvedilol can react with aldehydes or ester functional groups associated with conventionally used excipients, which may include esters, aldehydes and/or other chemical residue functional groups. This often results in marginal or unacceptable chemical stability upon storage.
US patent 2005/0277689 A1 describes the synthesis of carvedilol phosphate (II) carried out by treating carvedilol with o-phosphoric acid in acetone, acetone-water mixture to prepare the crystalline salt, and with methanol, isopropyl alcohol to prepare a solvate of carvedilol phosphate.
U.S. Patent Application 2005/0277689 A1 describes that carvedilol phosphate exhibits much higher aqueous solubility. A novel crystalline form is also disclosed having potential to improve the stability of carvedilol in formulations due to the fact that the secondary amine functional group attached to the carvedilol core structure, a moiety pivotal to degradation processes, is protonated as a salt.
In light of the foregoing, a salt, of carvedilol with greater aqueous solubility, chemical stability, etc. would offer many potential benefits for provision of medicinal products containing the drug carvedilol. Such benefits would include products with the ability to achieve desired or prolonged drug levels in a systemic system by sustaining absorption along the gastro-intestinal tract of mammals (i.e., such as humans), particularly in regions of neutral pH, where a drug, such as carvedilol, has minimal solubility.
The present invention is directed to providing another convenient and robust, rugged process for the preparation of carvedilol phosphate.